Margaret M. Briehl,
Assistant Professor of Pathology, Ph.D., University of Arizona, 1988
mmbriehl@u.arizona.edu

Relationship between oxidative stress, apoptosis and the development of cancer

Research Activities

Our long-term research objective is to understand the relationship between oxidative stress and disease processes, particularly cancer.  The objective of our current experiments is to determine the role of cellular redox state in the control of apoptosis.  The model system under study is glucocorticoid-induced apoptosis of a murine WEHI7.2 thymoma-derived cell line.  Our research results suggest that oxidative stress in this system is the result of hormone-mediated downregulation of the cellular antioxidant defense.  We have made oxidative stress-resistant WEHI7.2 cells through stable transfection with catalase cDNA and selection for resistance to hydrogen peroxide.  These variants show increased resistance to glucocorticoids. When implanted in SCID mice, the catalase transfected cells form tumors that grow at a faster rates than tumors from control cell implants.  The rate of apoptosis in the tumors is decreased, but there appears to be no difference in mitotic rate. This suggests that an increased antioxidant defense changes the redox state in the WEHI7.2 cells, which promotes faster tumor growth through an effect on apoptosis.  Additional studies in vitro have shown that the cytochrome c release is delayed in the catalase-transfected and hydrogen peroxide-resistant cells when they are exposed to glucocorticoids.  This suggest that the redox state plays a role in the signaling, rather than the execution, phase of apoptosis.  Future studies will be aimed at determining the exact mechanism by which an altered cellular redox state contributes to the control of apoptotic signaling.

Publications (Query PubMed for this investigator)

Tome, M.E., Baker, A.F., Powis, G., Payne, C.M. and Briehl, M.M. (2001) Catalase-overexpressing thymocytes are resistant to glucocorticoid-induced apoptosis and exhibit increased net tumor growth Cancer Res. 61:2766-2773

Dvorakova, K., Waltmire, C.N., Payne, C.M., Tome, M.E., Briehl, M.M., and Dorr, R.T. Induction of mitochondrial changes in myeloma cells by imexon. Blood 97:3544-3551

Siemankowski, L.M., Morreale, J., Butts, B.D. and Briehl, M.M. (2000) Increased tumor necrosis factor-ÿ sensitivity of MCF-7 cells transfected with NAD(P)H:quinone oxidoreductase. Cancer Res. 60:3638-3644

Briehl, M.M. (2000) Techniques for detection of apoptosis as an endpoint of oxidant exposure. In, Models and methods in cell signaling and gene expression: applications to oxidative stress research. Bray, T.M. and Schoene, N. (eds.) OICA International, London

Dvorakova, K., Payne, C.M., Tome, M.E., Briehl, M.M., McClure, T. and Dorr, R.T.:  Induction of oxidative stress and apoptosis in myeloma cells by aziridine-containing agent imexon. Biochem. Pharmacol. , in press, 2000.

Siemankowski, L.M., Morreale, J. and Briehl, M.M.:  Antioxidant defenses in TNF-treated MCF-7 cells: Selective increase in MnSOD. Free Radical Biol. Med., in press, 1999.

Yan, Q., Briehl, M., Crowley, C.L., Payne, C.M., Bernstein, H. and Bernstein, C.:  The NAD+ precursors, nicotinic acid and nicotinamide upregulate glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6 phosphate dehydrogenase (G6PD) mRNA in Jurkat cells. Biochem. Biophys. Res. Commun. 255:133-136, 1999.

Payne, C.M., Crowley, C., Washo-Stultz, D., Briehl, M., Bernstein, H., Bernstein, C., Beard, S., Holubec, H. and Warneke, J.:  The stress-response proteins poly(ADP-ribose) polymerase and NF-kB protect against bile salt-induced apoptosis. Cell Death Diff. 5:623-626, 1998.

Briehl, M.M., Baker, A.F. Siemankowski, L.M. and Morreale, J.:  Modulation of antioxidant defenses during apoptosis. Oncol. Res. 9:281-285, 1997.

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